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    Cardiovascular phenotypes in children with CKD: The 4C study
    (American Society of Nephrology, 2017) Schaefer F.; Doyon A.; Azukaitis K.; Bayazit A.; Canpolat N.; Duzova A.; Niemirska A.; Sözeri B.; Thurn D.; Anarat A.; Ranchin B.; Litwin M.; Caliskan S.; Candan C.; Baskin E.; Yilmaz E.; Mir S.; Kirchner M.; Sander A.; Haffner D.; Melk A.; Wühl E.; Shroff R.; Querfeld U.; 4C Study Consortium
    Background and objectives Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. Design, setting, participants, & measurements The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6–17 years old with initial GFR of 10–60 ml/min per 1.73 m2. The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intima-media thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers. Results A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level. Conclusions The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD. © 2016 by the American Society of Nephrology.
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    Childhood vasculitides in Turkey: A nationwide survey
    (2007) Ozen S.; Bakkaloglu A.; Dusunsel R.; Soylemezoglu O.; Ozaltin F.; Poyrazoglu H.; Kasapcopur O.; Ozkaya O.; Yalcinkaya F.; Balat A.; Kural N.; Donmez O.; Alpay H.; Anarat A.; Mir S.; Gur-Guven A.; Sonmez F.; Gok F.
    Aim: The aims of this study were to evaluate the characteristics of childhood vasculitides and to establish the first registry in Turkey, an eastern Mediterranean country with a white population. Patients and methods: A questionnaire was distributed to the main referral centers asking for the registration of the Henoch-Schönlein purpura (HSP) patients in the last calendar year only and 5 years for other vasculitides. Demographic, clinical, and laboratory data were assessed. Results: Vasculitic diseases were registered from 15 pediatric centers. These centers had a fair representation throughout the country. In the last calendar year, incidences were as follows: HSP 81.6%, Kawasaki disease (KD) 9.0%, childhood polyarteritis nodosa (C-PAN) 5.6%, Takayasu arteritis (TA) 1.5%, Wegener's granulomatosis 0.4%, and Behçet disease 1.9%. There was no clear gender dominance. The mean age was 11.05±4.89 years. Acute phase reactants were elevated in almost all, highest figures being in C-PAN. Renal involvement was present in 28.6% of HSP and 53% of the C-PAN patients. Abdominal aorta was involved in all TA patients. Among the C-PAN patients, 25% had microscopic PAN with necrotizing glomerulonephritis; antineutrophil cytoplasmic antibody was positive in those who were studied. Among the patients, 12.5% and 15% had classic PAN and cutaneous PAN, respectively. The remaining majority were classified as systemic C-PAN diagnosed with biopsies and/or angiograms demonstrating small to midsize artery involvement. The overall prognosis was better than reported in adult series. Conclusion: This is the largest multicenter study defining the demographic data for childhood vasculitides. The distribution of childhood vasculitides was different in our population where KD is much less frequent, whereas HSP constitutes an overwhelming majority. C-PAN was more frequent as well. © Clinical Rheumatology 2006.
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    Early proteinuria lowering by angiotensin-converting enzyme inhibition predicts renal survival in children with CKD
    (American Society of Nephrology, 2018) Van Den Belt S.M.; Heerspink H.J.L.; Gracchi V.; De Zeeuw D.; Wühl E.; Schaefer F.; Anarat A.; Bakkaloglu A.; Ozaltin F.; Peco-Antic A.; Querfeld U.; Gellermann J.; Sallay P.; Drozdz D.; Bonzel K.-E.; Wingen A.-M.; Zurowska A.; Balasz I.; Trivelli A.; Perfumo F.; Müller-Wiefel D.E.; Möller K.; Offner G.; Enke B.; Wühl E.; Gimpel C.; Mehls O.; Schaefer F.; Emre S.; Caliskan S.; Mir S.; Wygoda S.; Hohbach-Hohenfellner K.; Jeck N.; Klaus G.; Ardissino G.; Testa S.; Montini G.; Charbit M.; Niaudet P.; Caldas-Afonso A.; Fernandes-Teixeira A.; Dušek J.; Matteucci M.C.; Picca S.; Mastrostefano A.; Wigger M.; Berg U.B.; Celsi G.; Fischbach M.; Terzic J.; Fydryk J.; Urasinski T.; Coppo R.; Peruzzi L.; Arbeiter K.; Jankauskiené A.; Grenda R.; Litwin M.; Janas R.; Laube G.; Neuhaus T.J.
    Background Although pharmacotherapeutic proteinuria lowering was found to be nephroprotective in adults, the predictive value of early drug-induced proteinuria reduction for long-term renal survival in pediatric CKD is unknown. We analyzed data from the ESCAPE Trial for a potential association between initial antiproteinuric effect of standardized angiotensin-converting enzyme (ACE) inhibition and renal disease progression in children with CKD. Methods In total, 280 eligible children with CKD stages 2-4 (mean age 11.7 years old, median eGFR 46 ml/min per 1.73 m2, 71% congenital renal malformations) received a fixed dose of ramipril (6 mg/m2 per day) and were subsequently randomized to conventional or intensified BP control. We assessed initial proteinuria reduction from baseline to first measurement on ramipril (at 2.561.3 months). We used multivariable Cox modeling to estimate the association between initial proteinuria reduction and the risk of reaching a renal end point (50% eGFR decline or ESRD), which occurred in 80 patients during 5 years of observation. Results Ramipril therapy lowered proteinuria by a mean of 43.5% (95% confidence interval, 36.3% to 49.9%). Relative to proteinuria reduction,30%, 30%-60% and .60% reduction resulted in hazard ratios (95% confidence intervals) of 0.70 (0.40 to 1.22) and 0.42 (0.22 to 0.79), respectively. This association was independent of age, sex, CKD diagnosis, baseline eGFR, baseline proteinuria, initial BP, and concomitant BP reduction. Conclusions The early antiproteinuric effect of ACE inhibition is associated with long-term preservation of renal function in children with CKD. Proteinuria lowering should be considered an important target in the management of pediatric CKD. Copyright © 2018 by the American Society of Nephrology.
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    Genetic, environmental, and disease-associated correlates of vitamin D status in children with CKD
    (American Society of Nephrology, 2016) Doyon A.; Schmiedchen B.; Sander A.; Bayazit A.; Duzova A.; Canpolat N.; Thurn D.; Azukaitis K.; Anarat A.; Bacchetta J.; Mir S.; Shroff R.; Yilmaz E.; Candan C.; Kemper M.; Fischbach M.; Cortina G.; Klaus G.; Wuttke M.; Köttgen A.; Melk A.; Querfeld U.; Schaefer F.; 4C Study Consortium
    Background and objectives: Vitamin D deficiency is endemic in children with CKD.We sought to investigate the association of genetic disposition, environmental factors, vitamin D supplementation, and renal function on vitamin D status in children with CKD. Design, setting, participants, & measurements Serum: 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and 24,25-dihydroxy-vitamin D concentrations were measured cross-sectionally in 500 children from 12 European countries with CKD stages 3-5. All patients were participants of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study, had CKD stage 3-5, and were age 6-18 years old. Patients were genotyped for single-nucleotide polymorphisms in the genes encoding 25-hydroxylase, vitamin D binding protein, 7-dehydrocholesterol reductase, and 24-hydroxylase. Associations of genetic status, season, local solar radiation, oral vitamin D supplementation, and disease-associated factors with vitamin D status were assessed. Results: Two thirds of patientswere vitamin D deficient (25-hydroxy-vitamin D<16 ng/ml). 25-Hydroxy-vitamin D concentrations varied with season and were twofold higher in vitamin D-supplemented patients (21.6 [14.1] versus 10.4 [10.1] ng/ml; P<0.001). Glomerulopathy, albuminuria, and girls were associated with lower 25-hydroxy-vitamin D levels. 24,25-dihydroxy-vitamin D levels were closely correlated with 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D (r=0.87 and r=0.55; both P<0.001). 24,25-dihydroxy-vitamin D concentrations were higher with higher c-terminal fibroblast growth factor 23 and inversely correlated with intact parathyroid hormone. Whereas 25-hydroxy-vitamin D levels were independent of renal function, 24,25-dihydroxy-vitamin D levels were lower with lower eGFR. Vitamin D deficiency was more prevalent in Turkey than in other European regions independent of supplementation status and disease-related factors. Single-nucleotide polymorphisms in the vitamin D binding protein genewere independently associated with lower 25-hydroxy-vitamin Dand higher 24,25-dihydroxy-vitamin D. Conclusions: Disease-related factors and vitamin D supplementation are the main correlates of vitamin D status in children with CKD. Variants in the vitamin D binding protein showedweak associations with the vitamin D status. © 2016 by the American Society of Nephrology.
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    Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease
    (Springer Verlag, 2019) Holle J.; Querfeld U.; Kirchner M.; Anninos A.; Okun J.; Thurn-Valsassina D.; Bayazit A.; Niemirska A.; Canpolat N.; Bulut I.K.; Duzova A.; Anarat A.; Shroff R.; Bilginer Y.; Caliskan S.; Candan C.; Harambat J.; Özcakar Z.B.; Soylemezoglu O.; Tschumi S.; Habbig S.; Yilmaz E.; Balat A.; Zurowska A.; Cakar N.; Kranz B.; Ertan P.; Melk A.; Azukaitis K.; Schaefer F.
    Background: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients. Methods: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6–17 years with initial eGFR of 10–60 ml/min per 1.73 m2. Results: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 µmol/l (8.7) and 17.0 µmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors. Conclusions: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort. © 2019, IPNA.
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    Isolated nocturnal and isolated daytime hypertension associate with altered cardiovascular morphology and function in children with chronic kidney disease: Findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease study
    (Lippincott Williams and Wilkins, 2019) Düzova A.; Karabay Bayazit A.; Canpolat N.; Niemirska A.; Kaplan Bulut I.; Azukaitis K.; Karagoz T.; Oguz B.; Erdem S.; Anarat A.; Ranchin B.; Shroff R.; Djukic M.; Harambat J.; Yilmaz A.; Yildiz N.; Ozcakar B.; Büscher A.; Lugani F.; Wygoda S.; Tschumi S.; Zaloszyc A.; Jankauskiene A.; Laube G.; Galiano M.; Kirchner M.; Querfeld U.; Melk A.; Schaefer F.; Wühl E.
    Introduction:Prevalence of isolated nocturnal hypertension (INH) and isolated daytime hypertension (IDH) is around 10% in adults. Data in children, especially in chronic kidney disease (CKD), are lacking. The aim of this cross-sectional multicenter cohort study was to define the prevalence of INH and IDH and its association with cardiovascular morphology and function, that is, pulse wave velocity (PWV), carotid intima-media thickness (cIMT), or left ventricular mass index (LVMI) in children with CKD.Methods:Ambulatory blood pressure (BP) monitoring profiles were analyzed in 456 children with CKD stages III-V participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study (64.3% males, 71.3% congenital anomaly of the kidney and urinary tract, age 12.5 ± 3.2 years, estimated glomerular filtration rate 29 ± 12 ml/min per 1.73 m2). Baseline PWV, cIMT, and LVMI were compared in normotension, INH, IDH, or sustained 24-h hypertension.Results:Prevalence of sustained hypertension was 18.4%, of INH 13.4%, and of IDH 3.7%. PWV SDS (SD score) and cIMT SDS were significantly higher in sustained hypertension and INH, and PWV SDS was significantly higher in IDH, compared with normotension. LVMI was significantly increased in sustained hypertension, but not in INH or IDH. Determinants of INH were smallness for gestational age, older age, higher height SDS and parathyroid hormone, and shorter duration of CKD. In logistic regression analysis, day/night-time hypertension or ambulatory BP monitoring pattern (normal, INH, IDH, sustained hypertension) were independently associated with cardiovascular outcome measures: elevated night-time BP was associated with increased cIMT, PWV, and left ventricular hypertrophy; INH was associated with cIMT.Conclusion:INH is present in almost one out of seven children with predialysis CKD; INH and nocturnal hypertension in general are associated with alterations of arterial morphology and function. © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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    Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD
    (American Society of Nephrology, 2016) Shroff R.; Aitkenhead H.; Costa N.; Trivelli A.; Litwin M.; Picca S.; Anarat A.; Sallay P.; Ozaltin F.; Zurowska A.; Jankauskiene A.; Montini G.; Charbit M.; Schaefer F.; Wühl E.; Bakkaloglu A.; Peco-Antic A.; Querfeld U.; Gellermann J.; Drozdz D.; Bonzel K.-E.; Wingen A.-M.; Balasz I.; Perfumo F.; Müller-Wiefel D.E.; Möller K.; Offner G.; Enke B.; Gimpel C.; Mehls O.; Emre S.; Caliskan S.; Mir S.; Wygoda S.; Hohbach-Hohenfellner K.; Jeck N.; Klaus G.; Ardissino G.; Testa S.; Niaudet P.; Caldas-Afonso A.; Fernandes-Teixeira A.; Duek J.; Matteucci M.C.; Mastrostefano A.; Wigger M.; Berg U.B.; Celsi G.; Fischbach M.; Terzic J.; Fydryk J.; Urasinski T.; Coppo R.; Peruzzi L.; Arbeiter K.; Jankauskiené A.; Grenda R.; Janas R.; Laube G.; Neuhaus T.J.
    Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone system (RAAS) blockade are routinely used to slow CKD progression. However, Vitamin D may also promote renoprotection by suppressing renin transcription through cross-talk between RAAS and Vitamin D -fibroblast growth factor-23 (FGF-23)-Klotho pathways. To determine whether Vitamin D levels influence proteinuria and CKD progression in children, we performed a post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort. In 167 children (median EGFR 51 ml/min per 1.73 m2), serum 25-hydroxyvitaminD(25(OH)D),FGF-23, andKlotho levelsweremeasuredatbaselineandafteramedian8months onACEi.Childrenwith lower 25(OH)D levels had higher urinary protein/creatinine ratios at baseline (P=0.03) and at follow-up (P=0.006). Levels of 25(OH)D and serum Vitamin D -binding protein were not associated, but 25(OH)D #50 nmol/L associated with higher diastolicBP(P=0.004).ACEi therapy alsoassociatedwith increasedKlotho levels (P<0.001). The annualized loss of EGFR was inversely associated with baseline 25(OH)D level (P<0.001, r=0.32). Five-year renal survivalwas 75%in patientswith baseline 25(OH)D$50 nmol/L and 50%in thosewith lower 25(OH) D levels (P<0.001). This renoprotective effect remained significant but attenuated with ACEi therapy (P=0.05). Renal survival increased 8.2% per 10 nmol/L increase in 25(OH)D (P=0.03), independent of EGFR; proteinuria, BP, and FGF-23 levels; and underlying renal diagnosis. In children with CKD, 25(OH)D?50 nmol/L was associatedwith greater preservation of renal function. This effect was present but attenuated with concomitant ACEi therapy. © 2016 by the American Society of Nephrology.